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Treatment of Major Depressive DisorderSarah Mullowney, MD PGY3Psychiatry Resident, University of Utah
Paula Gibbs, MDMedical Director of 5 West at UUMCClerkship Director MS III Psychiatric RotationPsychiatrist for Project ECHO
Why does depression matter? Affects more than 300 million people worldwide
Leading cause of disability worldwide
Can be associated with medical comorbidity
Increased risk for suicide
Treatable
DSM-V Depressive Disorders Major depressive disorder
Persistent depressive disorder
Disruptive mood dysregulation disorder
Premenstrual dysphoric disorder
Substance/medication induced depressive disorder
Depressive disorder due to another medical condition
Unspecified depressive disorder
Diagnostic Criteria DSM V A. Five or more of the following symptoms have been present during the same two week
period and represent a change from a previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure.
Depressed mood nearly most of the day
Markedly diminished interest or pleasure in all or nearly all activities
Decrease or increased appetite or unintentional weight changes
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Worthless, useless, or excessively guilty feelings
�Decreased concentration or indecisiveness
�Suicidal thoughts or recurrent thoughts of death
SIG E CAPSSleepInterestGuiltEnergyConcentrationAppetitePsychomotor Suicidal thoughts
Diagnostic Criteria DSM V
B. These symptoms cause significant distress and impairment in social, occupational, or other areas of functioning.
C. The episode is not attributable to the physiological effects of substance abuse or to another medical condition.
Diagnostic Criteria DSM V D. the occurrence of the major depressive
episode is not better explained by schizoaffective disorder, schizophrenia, delusional disorder or other psychotic disorders
E. There has never been a manic episode or hypomanic episode
Diagnostic Criteria DSM V Specify:
With anxious distress
With mixed features
With melancholic features
With atypical features
With mood congruent psychotic features
With mood incongruent features
With catatonia
With peripartum onset
With a seasonal pattern
Epidemiology Lifetime Prevalence: 12% worldwide, 18% in the US
Females: 10-25%
Males: 5-12%
Point Prevalence:
Females 5-9%
Males: 2-3%
Mood disorders are highly prevalent and are among the top 10 causes of disability worldwide
Risk factors associated with MDD: gender, stressful life events, adverse childhood experiences, certain personality traits and positive FH
Clinical Course Mean age of onset: 29 years old
Only 57% of patients with MDD seek help and mostly consult with PCPs
Recurrent: 60-90% of MDD patients have 2 or more episode with partial or full interepisode remission
Chronic: 20% of MDD patients have an episode of 2 years or greater in duration
Mania: 5-10% of MDD patients have a subsequent manic or hypomanic episode(s)
Etiology of depression Genetic
Neurochemical
Psychological traits
Biological traits
Environmental / Social factors
Etiology Genetic:
Twin studies: MZ concordance rates are in the range of 30-50% and DZ concordance rates are in the range of 12-40% (female>male twins)
Twin adoption studies show 50-70% concordance for MDD in identical twins reared apart
First degree relative with MDD increase the risk threefold to fourfold
Neurochemical Basis of Depression Neurotransmitters implicated but not proven to
have a role:
Monoamines Serotonin, Norepinephrine, Dopamine deficiencies
GABA
Glutamate
HPA Axis implicated resulting in hypercortisolemia
Psychological Factors Distorted and negative patterns of thinking
Personality pathology
Neuroticism
Learned behaviors that reinforce depressive symptoms
Self-esteem
Management of losses and interpersonal relationships
Social Basis of Depression Recent stressors
Isolation
Poor social support
Depression in friends/family
History of trauma, especially during childhood
Parental loss
Low parental warmth
Marital problems
History of divorce
Low education
Treatment Psychotherapy
Biological treatments:
Medications
ECT
Vagal Nerve Stimulation
Transcranial Magnetic Stimulation
Combination treatment:
Psychotherapy and biological treatment
Psychotherapy Consensus is this is considered appropriate
monotherapy for mild to moderate non-psychotic MDD
Can be used as an augmentation agent with more severe depression
Proven modalities:
Cognitive-Behavioral Therapy
Interpersonal Psychotherapy
Common Medications Serotonin-Selective Reuptake Inhibitors (SSRIs)
Serotonin/Norepinephrine-Reuptake Inhibitors (SNRIs)
Others:
Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL)
Mirtazapine (Remeron)
Medications Antidepressant Indications:
Major Depressive Disorder (MDD)
Generalized Anxiety Disorder (GAD)
Panic Disorder (PD with or without agoraphobia)
Social Anxiety Disorder
Posttraumatic Stress Disorder (PTSD)
Obsessive-Compulsive Disorder (OCD)
Eating Disorder (Bulimia)
Borderline Personality Disorder (BPD)
NOTE: All antidepressants but Bupropion are indicated for the use in the above anxiety disorders and eating disorder (anorexia)
Medications SSRIs
Fluoxetine (Prozac) Long half life, increased energy, generally well tolerated
Sertraline (Zoloft) Low concentration in breastmilk, few drug interactions, generally well tolerated
Paroxetine (Paxil) Shorter half life, more side effects, many drug interactions
Citalopram (Celexa) Escitalopram (Lexapro)
Can initiate a therapeutic dose, generally well tolerated Fluvoxamine (Luvox)
Many drug interactions, most often used in OCD Vortioxetine (Trintellix)
Few side effects, some literature to suggest cognitive benefits Expensive
Vilazodone (Viibryd) Many side effects Expensive
Medications SNRI Duloxetine (Cymbalta) Helpful for chronic pain
Venlafaxine (Effexor) Increases energy Hypertension, short half life = risk for discontinuation
symptoms, difficult to taper to stop Desvenlafaxine (Prystiq) Increases energy Expensive, Hypertension, short half life = risk for
discontinuation symptoms, difficult to taper to stop Milnacipran (Savella) Indicated for chronic pain, not depression
Levomilnacipran (Fetzima) Expensive
Medications Other Mirtazapine (Remeron) Helpful for sleep
Bupropion (Wellbutrin) Increases energy, helps with smoking cessation,
can improve concentration (ADHD) Mild antidepressant, can make anxiety worse,
lowers seizure threshold Trazodone (Desyrel) Nefazodone (Serzone)
Medications Tricyclic Antidepressants Amitryptiline (Elavil) Helpful for sleep and chronic pain
Nortryptiline (Pamelor) Clomipramine (Anafranil) Most serotonergic, can be helpful for OCD
Desipramine (Norpramin) Doxepin (Silenor) Imipramine (Tofranil)
Medications MAOI Isocarboxazid (Marplan) Phenelzine (Nardil) Tranylcypromine (Parnate) Selegeline (Eldepryl, Zelapar) Selegeline transdermal (Emsam)
Antidepressant Prescribing Antidepressant List
University of Washington AIMS Center Prescriber’s Cheat Sheet
Side Effects Common SRI/SNRI side effects;
Nausea, diarrhea, dry mouth
Anxiety, insomnia, tremor/jitteriness
Fatigue, drowsiness, excessive sweating
Sexual dysfunction (decreased libido, delayed arousal, anorgasmia)
Apathy, emotional blunting
Weight gain (Paroxetine)
Hypertension (Venlafaxine)
Side Effects Uncommon SSRI/SNRI side effects:
Bruxism
Akathisia
Bruising/bleeding
Arthralgias
Suicidal ideation associated in the first several weeks of treatment and thereafter SI declining
Side Effects Bupropion:
All those of SRIs except sexual dysfunction
Constipation
Weight loss
Seizures especially in OD
Mirtazapine:
All those associated with SRIs except sexual dysfunction
Increased appetite and weight gain
Hypotension
Urinary frequency
Side Effects SRI/SNRI Discontinuation Syndrome:
Symptoms associated with the abrupt discontinuation of SRI/SNRI
Dizziness
Insomnia
Nervousness/anxiety
Irritability/agitation
Nausea
“Zappies”
Those medications with the shortest half life have a greater risk
Recommend taper off these medication to prevent
Medications SSRIs and half-life:
Fluoxetine (Prozac): 1-4 days
Paroxetine (Paxil): 20 hours
Sertraline (Zoloft): 26 hours
Citalopram (Celexa): 33 hours
Escitalopram (Lexapro): 33 hours
Fluvoxamine (Luvox): 16 hours
Vilazodone (Viibryd): 25 hours
Medications SNRIs and half life:
Venlafaxine (Effexor, Effexor XR): 5 hours and 11 hours
Duloxetine (Cymbalta): 12 hours
Desvenlafaxine (Pristiq): 11 hours
Levomilnacipran (Fetzima): 12 hours
Others:
Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL): 12 hours
Mirtazapine (Remeron) 20-40 hours
Medications Benefits of using non-TCA/MAOI Antidepressants:
Once daily dosing (except IR/SR Bupropion and IR Venlafaxine)
Low side effects and dropout rates
Low toxicity in OD
Effective in the treatment of different depressive subtypes
Effective in the treatment of comorbid anxiety disorders (except Bupropion)
Drug/Drug Interactions Use drug interaction checking tools
Many psychiatric medications are metabolized through the Cytochrome P450 system CYP 3A4 CYP 2D6 CYP 2C19
Can also act as inducers/inhibitors of these enzymes
Bupropion, sertraline, and trazodone have minimal CYP interactions
Drug-Drug Interactions Fluoxetine and paroxetine are CYP 2D6 inhibitors.
TCAs, antipsychotics, and antidepressants are often metabolized through CYP 2D6 and CYP2C19
Fluvoxamine – inhibitor of CYPs (1A2, 2C19, 3A4)
Nefazodone – Inhibitor of CYP3A4
Azoles (fluconazole) – inhibitor of CYP3A4
St. John’s Wort – inducer of CYP3A4
Carbamazepine, Phenytoin, Phenobarbital – inducer of CYP3A4
Rifampin – inducer of CYP3A4
Drug-Drug Interactions What will happen if…
Alprazolam (CYP3A4 substrate) + Fluvoxamine (CYP3A4 inhibitor)
Clozapine (CYP1A2 substrate) + smoking (CYP1A2 inducer)
Lithium + Ibuprofen
Diazepam (CYP3A4 substrate) + grapefruit juice (CYP3A4 inhibitor)
Amitriptyline (CYP2D6 substrate) + paroxetine (CYP2D6 inhibitor)
ECT Used for treatment resistant depression, psychotic
depression, treatment resistant bipolar disorder, catatonia, or if suicidal risk is deemed to be high even in an inpatient setting
80-95% effective
Expensive
Side effects are the side effects of seizures (HA, N,V, lethargy, short term memory loss) and general anesthesia
Clinical Pearls Do not under dose medications:
Titrate to the therapeutic dose
Slow titrations with patients with severe comorbid anxiety
Once at the therapeutic dose, if there is no response by 4-6 weeks:
Augment with second antidepressants outside the class, buspirone, Lithium, Atypical antipsychotics, Cytomel
Or switch to an antidepressant from another class
Clinical Pearls Use placebo effect to therapeutic advantage.
Length of depressive episode can indicate how well pt will respond to treatment
If the patient fails multiple trials of medications at the therapeutic dose and/or augmentation strategies:
Consider compliance issues
Add psychotherapy
Reconsider the diagnosis (Bipolar disorder or personality disorder)
Consider psychiatrist referral
Consider interventional treatments: ketamine/ECT/TMS
After remission is obtained, treatment should be continued at least 6 months, ideally 12 months, to limit risk of relapse
Recommended